BDNF - A key transducer of antidepressant effects

Carl Björkholm, Lisa M Monteggia

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.

Original languageEnglish (US)
Pages (from-to)72-79
Number of pages8
JournalNeuropharmacology
Volume102
DOIs
StatePublished - Mar 1 2016

Fingerprint

Brain-Derived Neurotrophic Factor
Transducers
Antidepressive Agents
Ketamine
Hippocampus
Knockout Mice
Elongation Factor 2 Kinase
Treatment-Resistant Depressive Disorder
Neuronal Plasticity
Nerve Growth Factors
Protein Biosynthesis
Prosencephalon
Neutralizing Antibodies
N-Methyl-D-Aspartate Receptors

Keywords

  • Behavior
  • Brain-derived neurotrophic factor
  • Depression
  • Hippocampus
  • Synaptic plasticity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

BDNF - A key transducer of antidepressant effects. / Björkholm, Carl; Monteggia, Lisa M.

In: Neuropharmacology, Vol. 102, 01.03.2016, p. 72-79.

Research output: Contribution to journalArticle

Björkholm, Carl ; Monteggia, Lisa M. / BDNF - A key transducer of antidepressant effects. In: Neuropharmacology. 2016 ; Vol. 102. pp. 72-79.
@article{ae2df65e3d964399ac4e5bf8505d646e,
title = "BDNF - A key transducer of antidepressant effects",
abstract = "How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.",
keywords = "Behavior, Brain-derived neurotrophic factor, Depression, Hippocampus, Synaptic plasticity",
author = "Carl Bj{\"o}rkholm and Monteggia, {Lisa M}",
year = "2016",
month = "3",
day = "1",
doi = "10.1016/j.neuropharm.2015.10.034",
language = "English (US)",
volume = "102",
pages = "72--79",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - BDNF - A key transducer of antidepressant effects

AU - Björkholm, Carl

AU - Monteggia, Lisa M

PY - 2016/3/1

Y1 - 2016/3/1

N2 - How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.

AB - How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.

KW - Behavior

KW - Brain-derived neurotrophic factor

KW - Depression

KW - Hippocampus

KW - Synaptic plasticity

UR - http://www.scopus.com/inward/record.url?scp=84946781732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946781732&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2015.10.034

DO - 10.1016/j.neuropharm.2015.10.034

M3 - Article

C2 - 26519901

AN - SCOPUS:84946781732

VL - 102

SP - 72

EP - 79

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -